An important source of individual variability in brain function supporting executive control is genetic variability in dopamine (DA) regulation. Extracellular DA levels vary by functional polymorphisms of clearance mechanisms: COMT (catechol-O-methyltransferase), an enzyme that degrades DA primarily in prefrontal cortex (PFC), has two genetic variants (Val, Met), and DAT (dopamine transporter), a protein that re-uptakes dopamine following release primarily in the striatum, has two common genetic variants (10-repeat, 9-repeat). Consistent with the importance of PFC-striatal circuits for executive operations such as working memory, independent, interactive, and additive effects of the two polymorphisms are apparent in functional activation during working memory. However, whether those genetic differences extend to functional connectivity during task performance and in the task-free, "resting state" is unknown. Slow spontaneous neural activity during rest (task-free state) is organized in networks comprising temporally correlated regions whose topography overlaps with task-evoked functional organization. The integrity of these networks predicts healthy attentional control and is disrupted in psychiatric disorders with executive dysfunction such as Schizophrenia and ADHD whose pathogenesis involves COMT and DAT genotypes, respectively. Thus, knowledge about genetic variability in healthy resting-state connectivity is important for suggesting neuroanatomical mechanisms of vulnerability to cognitive impairment associated with those disorders. We hypothesize that effects of COMT and DAT genotypes on functional connectivity will be paralleled in the task-evoked and resting- state in three networks, the task-negative network (default-mode) and two task-positive networks (executive control and salience). Healthy adults with combinations of COMT (Val/Val, Val/Met, Met/Met) and DAT (10/10, 9/10, 9/9) alleles will undergo fMRI during working memory (2-back vs. fixation) and during 5 mins of rest. Specific Aim 1 will examine differences by COMT and DAT alleles in activated (task-positive networks) and deactivated (task-negative network) regions and functional connectivity within each during working memory. We will examine independent and interactive (COMT X DAT ANOVA) and additive (regression analysis) effects of the genotypes. Specific Aim 2 will examine differences by COMT and DAT alleles in resting-state functional connectivity identified using seeds derived from Aim 1 (in confirmatory analysis) as well as using model-free Independent Components Analysis (in exploratory analysis), in collaboration with Dr. Vinod Menon. We expect to identify the same 3 networks as in Aim 1: 1) The task-negative network (medial PFC-posterior cingulate-hippocampus);2) Executive control network (dorsolateral PFC-lateral parietal);and 3) Salience network (anterior cingulate-insula-limbic). In both analyses, we will test for genotype differences as in Aim 1. These findings will be informative by extending current knowledge (connectivity during task-states) and breaking new ground (connectivity during resting-state). PUBLIC HEALTH RELEVANCE: This project aims to elucidate individual differences in functional brain organization and integrity of resting state connectivity associated with two genes controlling levels of dopamine, COMT Val158Met (catechol-O- methyltransferase) and DAT (dopamine transporter) in healthy adults. It will use functional magnetic resonance imaging to characterize brain activation and functional connectivity during working memory and while subjects rest with eyes closed. Knowledge gained from the proposed studies will suggest neuroanatomical hypotheses about vulnerability to cognitive dysfunction in disorders characterized by resting- state disturbances and associated with COMT and DAT such as Schizophrenia and Attention Deficit Hyperactivity Disorder, respectively.